Process for preparation of pyrazolo[4,3-d]pyrimidin-7-ones and intermediates thereof

ABSTRACT

A process is provided for the preparation of a compound of formulae (IA) (sidenafil) and (IB)  
                 
 
     comprising reacting a compound of formula (IIA) and (IIB) respectively in the presence of —OR, wherein R in the case of formation of compound (IA) is CH 2 CH 3  and R in the case of formation of compound (IB) is CH 2 CH 2 CH 3 , where X is a leaving group:

[0001] This invention relates to a process for the preparation of1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine(otherwiseknown as sildenafil or Viagra™), and1-Ethyl-4-{3-[3-ethyl-6,7-dihydro-7-oxo-2-(2-pyridylmethyl)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-4-propoxyphenylsulphonyl}piperazineand key intermediates thereof.

[0002]1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine(otherwise known as sildenafil) has been found to be particularly usefulin the treatment of, inter alia, male erectile dysfunction(WO-A-94/28907), and a process for its preparation is disclosed inEP-A-O463756 (example 12) and Drugs of the Future 1997, 22(2): 138-143.An improved process for preparing sildenafil (over that of EP0463756) isdisclosed in EP-A-O812845, with the characterising final step involvingcyclisation under basic, neutral or acidic conditions to formsildenafil. A process for the preparation of1-Ethyl-4-{3-[3-ethyl-6,7-dihydro-7-oxo-2-(2-pyridylmethyl)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-4-propoxyphenylsulphonyl}piperazineis disclosed in WO 98/49166 (example 5B).

[0003] The present inventors have now found a process for preparingsildenafil and1-Ethyl-4-{3-[3-ethyl-6,7-dihydro-7-oxo-2-(2-pyridylmethyl)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-4-propoxyphenylsulphonyl}piperazinewhich has advantages over the aforementioned prior art processes.

[0004] According to the present invention there is provided a processfor preparing a compound of formula (IA) and (IB)

[0005] comprising reacting a compound of (IIA) and (IIB) respectively inthe presence of ⁻OR, wherein R in the case of formation of compound (IA)is CH₂CH₃ and R in the case of formation of compound (IB) is CH₂CH₂CH₃,where X is a leaving group:

[0006] A particular advantage of the present process over that of theprior art is the elimination of steps by carrying out a substitutionreaction and ring closure in ‘one pot’.

[0007] The intermediates of general formula (IIA) and (IIB) form afurther aspect of the invention.

[0008] A key intermediate of the general formula (IIIA) and (IIIB) (seeschemes 1 and 2 hereafter) have been identified in various reactionsshowing that such reactions at least partially go via a pathway ofcyclisation then nucleophilic substitution. Accordingly intermediates ofgeneral formula (IIIA) and (IIIB) form yet a further aspect of theinvention (wherein X is a leaving group).

[0009] A further major intermediate of formula IVA and IVB have alsobeen identified, suggesting that there is also nucleophilic substitutionbefore cyclisation (and these intermediates, where novel, form a furtheraspect of the invention).

[0010] Thus the proposed reaction pathways for the formation ofcompounds (IA) and (IB) are as follows

[0011] The relative proportion of intermediates formed is partiallydependent on the nature of X (the leaving group).

[0012] Preferably X is selected from the group consisting of optionallysubstituted arylsulphonyloxy, preferably phenylsulphonyloxy, morepreferably a para substituted aryl (phenyl) such as by a C₁-C₄ alkylgroup e.g. p-toluenesulphonyloxy; C₁-C₄ alkylsulphonyloxy e.g.methanesulphonyloxy; nitro or halo substituted benzenesulphonyloxypreferably para substituted e.g. p-bromobenzenesulfonyloxy orp-nitrobenzenesulphonyloxy; C₁-C₄ perfluoroalkylsulphonyloxy e.g.trifluoromethylsulphonyloxy; optionally substituted aroyloxy such asbenzoyloxy; C₁-C₄ perfluoroalkanoyloxy such as trifluoroacetyloxy; C₁-C₄alkanoyloxy such as acetyloxy; halo; diazonium; C₁-C₄ primary andsecondary alkoxy such as methoxy; oxonium; perchloryloxy;quatenaryammonium C₁-C₄ alkylsulphonyloxy; halosulphonyloxy e.g.fluorosulphonyloxy and other fluorinated leaving groups; halonium; anddiarylsulphonylamino e.g. ditosyl (NTs₂).

[0013] Suitably X is a halo (fluoro, chloro, bromo or iodo) or methoxy,and most suitably it is fluoro or chloro. The latter have been found toprovide particularly good yields, and inexpensive commercially availablestarting materials (chloro and fluoro benzoic acid) can readily be used.

[0014] Herein ⁻OCH₂CH₃ and ⁻OCH₂CH₂CH₃ (disclosed in the first aspect ofthe invention) are referred to for convenience as ⁻OR. ⁻OR can act asboth a nucleophile (to displace the leaving group by nucleophilicsubstitution) and as a base (to bring about the cyclisation). ⁻OR can begenerated in solution from, a salt ZOR (wherein Z is a cation) such as ametal salt. More particularly an alkali (such as sodium or potassium) oralkaline earth metal salt of ⁻OR in a suitable solvent would give riseto ⁻OR in solution. For example sodium ethoxide (Na⁺⁻ OEt) in a suitablesolvent with intermediate (IIA) would form sildenafil. In anotherembodiment, ⁻OR is formed insitu from ROH plus an auxiliary base (i.e. abase other than ⁻OR). However, in another system, ZOR could be used inthe reaction system with an auxiliary base.

[0015] Preferred Embodiments of the Invention Are:

[0016] 1. the synthesis of compound (IA) by reaction of compound (IIA):

[0017] a) with ethanol and auxiliary base, optionally in an inertsolvent;

[0018] b) with ZOEt and an auxiliary base in ethanol or an inert solventor both;

[0019] c) with ZOEt and ethanol or an inert solvent or both. thesynthesis of compound (IB) by reaction of compound (IIB):

[0020] d) with propanol and auxiliary base, optionally in an inertsolvent;

[0021] e) with ZOPr and an auxiliary base, in propanol or an inertsolvent or both;

[0022] f) with ZOPr, and propanol or an inert solvent or both.

[0023] As will be appreciated the solvent in which the reaction takesplace can be ROH or an inert solvent (or a mixture of both). By inertsolvent we mean a solvent which will not form a nucleophile under thereaction conditions or if a nucleophile is formed it is sufficientlyhindered such that it does not substantially compete in the displacementreaction. When ROH is used as a source of ⁻OR, then a separate solventis not essentially required but an (auxiliary) inert solvent (i.e. asolvent other than ROH) may be used as a co-solvent in the reaction.

[0024] Suitable Solvents are as Follows: ethanol (for IA), propanol (forIB) (n-propanol), a secondary or tertiary C₄-C₁₂ alkanol, a C₃-C₁₂cycloalkanol, a tertiary C₄-C₁₂ cycloalkanol, a secondary or tertiary(C₃-C₇ cycloalkyl)C₂-C₆ alkanol, a C₃-C₉ alkanone, 1,2-dimethoxyethane,1,2-diethoxyethane, diglyme, tetrahydrofuran, 1,4-dioxan, toluene,xylene, chlorobenzene, 1,2-dichlorobenzene, acetonitrile, dimethylsulphoxide, sulpholane, dimethylformamide, N-methylpyrrolidin-2-one,pyridine, and mixtures thereof.

[0025] A wide range of auxiliary bases can be used in the process of theinvention. Typically the bases would not compete with ⁻OR in thenucleophilic substitution of X (i.e. they would be non nucleophilic) bysuitably being sterically hindered. Preferred bases in accordance withthe invention are selected from the group consisting of metal salts of asterically hindered alcohol or amine such as a secondary or tertiaryC₄-C₁₂ alkanol, a C₃-C₁₂ cycloalkanol and a secondary or teritary (C₃-C₈cycloalkyl)C₁-C₆ alkanol, a N-(secondary or tertiary C₃-C₆alkyl)-N-(primary, secondary or tertiary C₃-C₆ alkyl)amine, a N-(C₃-C₈cycloalkyl)-N-(primary, secondary or tertiary C₃-C₆ alkyl)amine, adi(C₃-C₈ cycloalkyl)amine or hexamethyldisilazane; metal salts of1-methyl piperazine (especially for compound IA), 1-ethylpiperazine(especially for compound IB), and morpholine;1,5-diazabicyclo[4,3,0]non-5-ene and 1,8-diazabicyclo[5,4,0]undec-7-ene;tertiary amines such as triethylamine; metal hydride, oxide, carbonate,and bicarbonate.

[0026] Preferably the metal of the salt of ZOR and the auxiliary baseare independently selected from alkali metals (lithium, sodium,potassium, rubidium, caesium) or alkaline earth metals (beryllium,magnesium, calcium, strontium, barium). More preferably the metal issodium or potassium.

[0027] Preferably the auxiliary base is selected from the groupconsisting of metal salts of a sterically hindered alcohol or amine suchas a secondary or tertiary C₄-C₁₂ alkanol, a C₃-C₁₂ cycloalkanol and asecondary or tertiary (C₃-C₈ cycloalkyl)C₁-C₆ alkanol, a N-(secondary ortertiary C₃-C₆ alkyl)-N-(primary, secondary or tertiary C₃-C₆alkyl)amine, a N-(C₃-C₈ cycloalkyl)-N-(primary, secondary or tertiaryC₃-C₆ (alkyl)amine, a di(C₃-C₈ cycloalkyl)amine or hexamethyldisilazane;1,5-diazabicyclo[4,3,0]non-5-ene and 1,8-diazabicyclo[5,4,0]undec-7-ene;metal hydride, oxide, carbonate and bicarbonate.

[0028] More preferably still, the auxiliary base is selected from thesterically hindered bases of the previous paragraph (i.e. all of themexcept the metal hydride, oxide, carbonate and bicarbonate).

[0029] Most preferably the auxiliary base is the metal salt of atertiary C₄-C₆ alcohol such as the alkali or alkaline earth metal salts(e.g. Na/K) of t-butanol or t-amyl alcohol.

[0030] To maximise yields, it is further preferred that at least onemolecular equivalent (suitably one and a half equivalent) of auxiliarybase and ⁻OR are used in accordance with the invention. If ⁻OR alsofunctions as a base then preferably at least two equivalents, (morepreferably three equivalents) of ⁻OR are present. Thus for example inpreferred embodiments (a) to (f) above, preferably there is at least 2equivalents of auxiliary base and at least one equivalent of EtOH orPrOH (a and d respectively ), preferably at least 1 equivalent ofauxiliary base and at least 1 equivalent of ZOEt or ZOPr (b and erespectively) and preferably at least 2 equivalents of ZOEt or ZOPr (cand f respectively). These are equivalents with respect to the molarquantities of IIA or IIB.

[0031] The nature of the leaving group (X) may influence the reactionpathway. For example with reference to scheme 1 for compound (IA), whenX=F the reaction mostly proceeds via the intermediate illustrated by(IVA) but when the X=Cl the pathway shifts more towards the intermediateof (IIIA), and when X=OCH₃ there is more of the formula (IIIA)intermediate formed than the formula (IVA) type intermediate. However,formation of the final compound of formulae (IA) and (IB) from theintermediate formulae (IIIA) and (IIIB) respectively can be encouragedby using a higher temperature and allowing more time for formation ofthe final product.

[0032] Preferably the general reaction is carried out at from 50° C. to170° C. Thus where X=F, the reaction temperature could be anything fromabout 50° C., preferably 60° C. upward and the rate of formation of thefinal product would be very good. For X=Cl, preferably a temperature of60 to 170° C., more suitably at least 80° C. such as (80° C. to 110° C.) would increase the rate; and for X=OCH₃, preferably a temperature ofat least 80° C., more suitably at least 110° C. (such as 110° C. to 140°C.) would increase the rate to the final product.

[0033] The compounds of general formula (IIA) and (IIB) may be obtainedfrom readily available starting materials for example, by the routedepicted in the following reaction schemes. Reaction scheme 3 isillustrated for compound (IA) and scheme 4 is illustrated for compound(IB).

[0034] With reference to scheme 3, the intermediate of formula (VIA) isformed from a substituted (i.e. group X) benzoic acid derivative byreaction with chlorosulphonic acid. Intermediate (VIA) is then reactedwith N-methylpiperazine in the presence of a base, such as a tertiaryamine, more particularly triethylamine and a suitable solvent such asacetone or water to form intermediate (VIIA).

[0035] (IIA) is formed by reaction of intermediate (VIIA) and4-amino-1-methyl-3-propyl-1H-pyrazole -5-carboxamide (compound IXA) inthe presence of a coupling agent, such as1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride and wheredesirable also in the presence of a base and/or an accelerator. In oneexample of a coupling system, the carboxylic acid function of (VIIA) isfirst of all activitated using about a 5% excess of a reagent such asN,N-carbonyldimidazole (as coupling agent) in a suitable solvent, e.g.ethyl acetate, at from about room temperature to about 80° C., followedby reaction of the intermediate imidazolide with (IXA) at from about 20to about 60° C. In another example, intermediate (VIIA) could be coupledto the pyrazole (IXA) in the presence of 1-hydroxybenzotriazole,triethylamine and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimidehydrochloride.

[0036] Compound (IXA) is formed by reducing 1-methyl-4nitro-3-propyl-1H-pyrazole-5 carboxamide (VIIA) such as by hydrogenationin the presence of 5% palladium on charcoal.

[0037] Compound (IB) (scheme 4) can be formed in an analogous fashion tothat of compound (IA). More particularly, intermediate (VIIB) isprepared by reacting (VIA) with N-ethylpiperazine; and intermediate(IIB) is formed by coupling intermediate compounds (VIIB) and (IXB).

[0038] The intermediates of general formulae (VIIA) and (VIIB) are noveland form a further aspect of the invention (wherein X is as definedhereinbefore)

[0039] The invention will now be described by way of example only withreference to the following examples.

EXAMPLE 1

[0040] (1a) 5-Chlorosulphonyl-2-fluorobenzoic acid (Compound VIA, X=F)

[0041] Commercially available 2-fluorobenzoic acid (75 g, 0.54 Mol) wasadded to chlorosulphonic acid (320 g ) over 15 minutes, stirred for 30minutes then heated to 90° C. for 4½ hrs. Once cool, the reaction wasquenched onto ice/water (1.5 kg/324 ml) and granulated for 1 hr. Theprecipitated product was filtered, water washed and dried at 50° C.under vacuo to give the title compound (99.7 g, 78.1%) as a white solid.

[0042] (1b) 2-Fluoro-5-(4-methyl-1-piperazinylsulphonyl)benzoic acid(Compound VIIA, X=F)

[0043] A solution of 5-chlorosulphonyl-2-fluorobenzoic acid (47.72 g,0.2 mol) in acetone (250 ml) was added to a mixture ofN-methylpiperazine (22.04 g, 0.22 mol) and triethylamine (24.29 g, 0.24mol) and the reaction was stirred at ambient for three hours. Themixture was filtered, the resulting solid was recrystallised from waterto afford the title compound (14.63 g, 24.2%) as a white solid. δ(DMSO): 2.30 (3H, s), 2.58 (4H, m), 2.95 (4H, m), 7.52 (1H, m), 7.90(1H, m), 8.10 m/z (Found: 303 [M+H]⁺, 100%, C₁₂H₁₆FN₂O₄S requires 303).

[0044] (1c) 4-Amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide

[0045] A stirred suspenson of1-methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxamide (EP-A-0463756; 237.7g, 1.12 mol) and 5% palladium on charcoal (47.5 g) in ethyl acetate(2.02 1) was hydrogenated at 344.7 kPa (50 psi) and 50° C. for 4 hours,when the uptake of hydrogen was complete. The cool reaction mixture wasfiltered, then the filter pad washed with ethyl acetate, the combinedfiltrate and washings thus furnishing an ethyl acetate solution of thetitle compound (EP-A-0463756) which was of sufficient purity to usedirectly in the next stage of the reaction sequence.

[0046] (1d)4-[2-Fluoro-5-(4-methyl-1-piperazinylsulphonyl)benzamido]-1-methyl-3-propyl-1H-pyrazole-5-carboxamide.(CompoundIIA, X=F)

[0047] 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide (1.27 g, 6.94mmol) was added to a suspension of2-fluoro-5-(4-methyl-1-piperazinylsulphonyl)benzoic acid (2.0 g, 6.94mmol ), triethylamine (0.70 g, 6.92 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.33 g,6.94 mmol) and 1-hydroxybenzotriazole (0.94 g, 6.96 mmol) in a mixtureof ethyl acetate (20 ml) and dichloromethane (20 ml). The reactionmixture was stirred for 12 hours at ambient temperature. The reactionmixture was stripped down to an oil and purified using columnchromatography (flash silica, 30:70, methanol:ethyl acetate). The titlecompound of preparation was further purified by dissolving indichloromethane and washing with saturated sodium bicarbonate solution.The organic solution was stripped down under vacuum to produce a solidwhich was dried (40° C.) to afford the title compound (2.1 g, 64.8%) asa white solid. m.p. 210-212° C. Found: C.51.15; H, 5.81; N, 17.90.C₂₀H₂₇FN₆O₄S requires C, 51.49; H, 5.83; N, 18.01. δ(CDCl₃): 0.95 (3H,t), 1.62 (2H, m), 2.30 (3H, s), 2.50 (6H, m), 3.10 (4H, m), 4.10 (3H,s), 7.41 (1H, m), 8.00 (2H, m), 8.50 (1H, m). m/z (Found: 467.18909([M+H]⁺, 37%), C₂₀H₂₈N₆ _(O) ₄SF requires 467.1890).

[0048] (1e)1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine.(Compound IA)

[0049] Potassium t-butoxide (0.74 g, 6.60 mmol) was added to asuspension of the title compound of example (1d) (1.00 g, 2.20 mmol) inethanol (5 ml) and the mixture was heated under reflux for 48 hours. Thereaction mixture was stripped down to an oil and purified by dissolvingin dichloromethane and washing with saturated sodium bicarbonatesolution. Hexane was added to the organic solution over 10 minutes, aprecipitated solid filtered and dried to afford the title compound (1.1g,100%) as a white solid. Recrystallisation of the title compound fromethyl acetate affords a solid with m.p.184-186° C. Found: C, 55.49; H,6.35; N, 17.72. C₂₂H₃₁N₆O₄S requires C, 55.58; H, 6.53; N, 17.68. δ(DMSO): 0.96 (3H, t), 1.30 (3H, t), 1.72 (2H, m), 2.13 (3H, s), 2.36(4H, m), 2.72 (2H, t), 2.90 (4H, m), 4.18 (5H, m), 7.32 (1H, d), 7.80(2H, m) m/z (Found: 475.214800 ([M+H]⁺, 100%). C₂₂H₃₁N₆O₄S. requires475.212751).

[0050] The reaction went almost entirely via intermediate IVA, and wentto completion in less than 48 hours.

EXAMPLE 2

[0051] (2a) 2-Chloro-5-chlorosulphonylbenzoic acid (Compound VIA, X=Cl)

[0052] Commerically available 2-chlorobenzoic acid (80.0 g), (0.5 mol),was added portionwise to chlorosulphonic acid (320 g) with vigorousstirring. The reaction was heated to 95° C. for 6 hrs then cooledovernight to room temperature. The solution was quenched onto ice/water(1.5 kg/324 ml) and stirred for 15 min. The precipitated product wasfiltered, water washed and dried at 50° C. in vacuo, to give the titlecompound (111.1 g, 85.2%) as a white solid with m.p. 140° C. δ (CDCl₃):7.42 (1H,m), 8.27 (1H,m), 8.75 (1H,m).

[0053] (2b) 2-Chloro-5-(4-methyl-1-piperazinylsulphonyl)benzoic acid(Compound VIIA, X=Cl)

[0054] The above compound was prepared by adding2-chloro-5-chlorosulphonylbenzoic acid to 1.25 mol equivalent ofN-ethylpiperazine in water (3 ml/g) under acidic conditions.

[0055] The title compound was then isolated as a solid (81.7%).Recrystallisation of the title compound from acetone: water affords asolid with m.p. 304-6° C., and the following characteristic data: Found:C, 45.16; H, 4.71; N, 8.64. C₁₂H₁₅ClN₂O₄S requires C, 45.21; H, 4.71; N,8.79. δ (DMSO): 2.20 (3H, s), 2.50 (4H, m), 2.95 (4H, m), 6.75 (2H, m),9.95 (1H, s), m/z (Found: 319 [M+H]⁺, 100% C₁₂H₁₆ClN₂O₄S requires 319).

[0056] (2c)4-[2-Chloro-5-(4-methyl-1-piperazinylsulphonyl)benzamido]-1-methyl-3-propyl-1H-pyrazole-5-carboxamide.(Compound IIA, X=Cl)

[0057] 4-Amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide (2.86 g,15.68 mmol) (example 1c) was added to a suspension of2-chloro-5-(4-methyl-1-piperazinylsulphonyl) benzoic acid (5.0 g, 15.68mmol), triethylamine (1.59 g, 15.68 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.00 g,15.68 mmol), and 1-hydroxybenzotriazole (2.12 g, 15.68 mmol) indichloromethane (50 ml). The reaction was stirred for 48 hours atambient temperature, a further portion of1-(3-dimethylaminopropyl)-3-ethyl carbodimide hydrochloride (1.00 g, 5.2mmol) added and the reaction stirred for a further 48 hours at ambienttemperature. The reaction mixture was washed with saturated sodiumbicarbonate solution and ethyl acetate added to the separated organicsolution over ten minutes. The mixture was stirred for ten minutes and aprecipitated solid filtered, and dried to afford the title compound (6.0g , 81%). m.p 105-107° C. δ (DMSO): 0.90 (3H, t), 1.60 (2H, m), 2.13(3H, s), 2.40 (4H, m), 2.50 (2H, m), 2.95 (4H, m), 3.90 (3H, s), 7.30(1H, s), 7.82 (4H, m), 10.0 (1H, s). m/z (Found: 505.140303 ([M+Na]⁺,28%). C₂₀H₂₇ClN₆O₄SNa. requires 505.140073).

[0058] (2d)1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine.(Compound IA)

[0059] Potassium t-butoxide (1.43 g, 12.75 mmol) was added to asuspension of the title compound of example 2(c) (2.00 g, 4.25 mmol) inethanol (20 ml) and the mixture was heated under reflux for 48 hours.The pH of the reaction was adjusted to 6, using 1N hydrochloric acid,the precipitated solid filtered and dried to afford the title compound.Recrystallisation of the title compound from methyl isobutyl ketoneafforded a solid with m.p 188° C. δ (CDCl₃): 1.01 (3H, t), 1.62 (3H, t),1.88 (2H, m), 2.30 (3H, s), 2.50 (4H, m), 2.95 (2H, t), 3.13 (4H, m),4.30 (3H, s), 4.39 (2H, q) 7.15 (1H, d), 7.82 (1H, m), 8.82 (1H, m). m/z(Found: 475.2127 ([M+H]⁺, 100%). C₂₂H₃₁N₆O₄S. requires 475.212751).

[0060] Intermediate of formula IVA was prepared in accordance withEP-A-0812845, and intermediate of formula IIIA, X=Cl was prepared inaccordance with example 2(e) herebelow. These intermediates were thenused as markers for comparison of hplc samples taken from the reactionmixture during step 2(d), in order to deduce the reaction path.

[0061] Intermediates IIIA (X=Cl) and IVA were observed (by hplc) in aratio of about 20:80 respectively.

[0062] 2(e):1-[4-Chloro-3-(6,7-dihydro-1-methyl-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenylsulphonyl]-4-methylpiperazine,(Compound IIIA, X=Cl)

[0063] Potassium t-butoxide (0.24 g, 2.14 mmol) was added to asuspension of the title compound of example 2(c) (1.00 g, 2.12 mmol) int-butanol (5 ml) and the mixture was heated under reflux for 120 hours.The reaction mixture was cooled and the precipitated solid was filteredand dried to afford the title compound (0.48 g, 50%) as a white solidm.p. 205-208° C. δ (DMSO): 0.90 (3H, t), 1.70 (2H, m), 2.13 (3H, s),2.38 (4H, m), 2.68 (2H, t), 2.92 (4H, m) 4.10 (3H, s), 4.15 (1H, s),7.60 (1H, m), 7.70 (1H, d), 7.85 (1H, m). m/z (Found: 465.1484 ([M+H]⁺,100%). C₂₀H₂₆ClN₆O₃S requires 465.147564).

EXAMPLE 3

[0064] (3a) 5-Chlorosulphonyl-2-methoxybenzoic acid (Compound VIA,X=OCH₃)

[0065] Commercially available 2-methoxybenzoic acid (15.2 g, 0.1 mol)was added portionwise to chlorosulphonic acid (52.43 g ) over 30 minwith ice cooling. Thionyl chloride (11.9 g, 0.1 mol) was added and thereaction stirred overnight. The reaction was quenched onto ice/water(250 g/65 ml) and the precipitated product granulated for 1 hr,filtered, water washed and oven dried to give the title compound (23.56g, 93.9%) as a white solid with m.p. 138-140° C. δ (CDCl₃): 4.18 (3H,s), 7.23 (1H, d), 8.21 (1H, d), 8.78 (1H, s).

[0066] (3b) 2-Methoxy-5-(4-methyl-1-piperazinylsulphonyl)benzoic acid

[0067] The above compound was prepared by adding5-chlorosulphonyl-2-methoxybenzoic acid to 1.1 mol equivalent ofN-methylpiperazine and 1.2 mol equivalents of triethylamine in acetone(5 ml/g).

[0068] The title compound was then isolated by filtration, as a solid(79.1%), with the following characteristic data: Found: C, 49.70; H,5.76; N, 8.75. C₁₃H₁₈N₂O₅S requires C, 49.68; H, 5.73; N, 8.92. δ(DMSO): 2.15 (3H, s), 2.35 (4H, m), 2.90 (4H, m), 3.90 (3H, s), 7.25(1H, m), 7.10 (2H, m), m/z (Found: 315 [M+H]⁺, 65% C₁₃H₁₉N₂O₅S requires315).

[0069] (3c)4-[2-Methoxy-5-(4-methyl-1-piperazinylsulphonyl)benzamido]-1-methyl-3-propyl-1H-pyrazole-5-carboxamide.(Compound IIA X=OCH₃)

[0070] A mixture of 2-methoxy-5-(4-methyl-1-piperazinylsulphonyl)benzoicacid (2.00 g, 6.36 mmol) and carbonyl diimidazole (1.03 g, 6.35 mmol) indichloromethane (20 ml) was stirred for three hours at 30° C.4-Amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide (1.16 g, 6.37 mmol)and triethylamine (0.64 g, 6.32 mmol) were added to the reaction mixtureand stirred for 48 hours at ambient temperature. The reaction mixturewas washed with saturated sodium bicarbonate solution, the separatedorganic solution stripped under vacuum to produce a solid which wasdried (40° C.) to afford the title compound (2.74 g, 90%) as a whitesolid. m.p. 182° C. Found: C, 52.42; H, 6.36; N, 17.31; C₂₁H₃₀N₆O₅Srequires C, 52.71; H, 6.32; N, 17.56. δ (DMSO): 0.90 (3H, t), 1.60 (2H,m), 2.12 (3H, s), 2.32 (4H, m), 2.42 (2H, t), 2.90 (4H, m), 3.90 (3H,s), 4.00 (3H, s), 7.32 (1H, s) 7.42 (1H, d), 7.80 (1H, s), 7.90 (2H, m),9.70 (1H, s). m/z (Found: 479.2088 ([M+H]⁺, 52%). C₂₁H₃₁N₆O₅S. requires479.207665).

[0071] (3d)1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine.(Compound IA)

[0072] Potassium-t-butoxide (146 mg,1.30 mmol) was added to a suspensionof the title compound of step 3c (200 mg, 0.43 mmol) in ethanol (4 ml)and the mixture was heated under reflux for 120 hours. The reactionmixture was cooled and the pH of the reaction was adjusted to 6, usingdilute hydrochloric acid. The precipitated solid was filtered and driedto afford the title compound (60 mg, 29%) as an off white solid withm.p. 187° C. δ (CDCl₃): 1.00 (3H, t), 1.62 (3H, t), 1.90 (2H, m), 2.22(3H, s), 2.50 (4H, m), 2.95 (2H, t), 3.10 (4H, m), 4.30 (3H, s), 4.38(2H, q), 7.15 (1H, d), 7.82 (1H, d), 8.82 (1H, s), 10.85 (1H, s). m/z(Found: 497.199635 [M⁺, 100%]. C₂₂H₃₀N₆O₄S. requires 497.194695).

[0073] The following intermediate 3(e) was independently prepared andused as a marker for hplc comparison of samples taken from the reactionmixture during step 3(d).

[0074] The intermediate of example 3(e) (IIIA, X=OCH₃) and intermediateIVA were observed by hplc in a ratio of about 70:30 respectively.

[0075] (3e)1-[3-(6,7-Dihydro-1-methyl-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)4-methoxy-phenylsulphonyl]-4-methylpiperazine(Compound IIIA, X=OCH₃)

[0076] Potassium t-butoxide (0.176 g, 1.57 mmol) was added to asuspension of the title compound of step 3c (0.75 g, 1.57 mmol) int-butanol (5 ml) and the mixture was heated under reflux for 96 hours.The reaction mixture was cooled and the precipitated solid was filteredand dried to afford the title compound (0.33 g, 45.6%) as a white solidm.p. 182° C. δ (CDCl₃): 1.02 (3H, t), 1.88 (2H, m), 2.30 (3H, s), 2.50(4H, m), 2.92 (2H, t), 3.10 (4H, m), 4.15 (3H, s), 4.30 (3H, s), 7.20(1H, m), 7.95 (1H, d), 8.10 (1H, m).

EXAMPLE 4

[0077] (4a) Ethyl 3-ethyl-1H-pyrazole-5-carboxylate

[0078] Ethanolic sodium ethoxide solution (21% w/w; 143 ml, 0.39 mol)was added dropwise to a stirred, ice-cooled solution of diethyl oxalate(59.8 ml, 0.44 mol) in absolute ethanol (200 ml) under nitrogen and theresulting solution stirred for 15 minutes. Butan-2-one (39 ml, 0.44 mol)was then added dropwise, the cooling bath removed, the reaction mixturestirred for 18 hours at room temperature and then for 6 hours at 40° C.,then the cooling bath reintroduced. Next, glacial acetic acid (25 ml,0.44 mol) was added dropwise, the resulting solution stirred for 30minutes at 0° C., hydrazine hydrate (20 ml, 0.44 mol) added dropwise,then the reaction mixture allowed to warm to room temperature andmaintained there over a period of 18 hours, before being evaporatedunder reduced pressure. The residue was partitioned betweendichloromethane (300 ml) and water (100 ml), then the organic phaseseparated, washed with water (2×100 ml), dried (Na₂SO₄) and concentratedunder reduced pressure to give the title compound (66.0 g ). δ (CDCl₃):1.04 (3H,t), 1.16 (3H,t), 2.70 (2H,q), 4.36 (2H,q), 6.60 (1H,s). LRMS:m/z 169 (M+1)⁺.

[0079] (4b) 3-Ethyl-1H-pyrazole-5-carboxylic acid

[0080] Aqueous sodium hydroxide solution (10M; 100 ml, 1.0 mol) wasadded dropwise to a stirred suspension of the title compound of example(4a) (66.0 g, 0.39 mol) in methanol and the resulting solution heatedunder reflux for 4 hours. The cool reaction mixture was concentratedunder reduced pressure to ca. 200 ml, diluted with water (200 ml) andthis mixture washed with toluene (3×100 ml). The resulting aqueous phasewas acidified with concentrated hydrochloric acid to pH 4 and the whiteprecipitate collected and dried by suction to provide the title compound(34.1 g ). δ (DMSO_(d6)): 1.13 (3H,t), 2.56 (2H,q), 6.42 (1H,s).

[0081] (4c) 3-Ethyl-4-nitro-1H-pyrazole-5-carboxylic acid

[0082] Fuming sulphuric acid (17.8 ml) was added dropwise to stirred,ice-cooled fuming nitric acid (16.0 ml), the resulting solution heatedto 50° C., 3-ethyl-1H-pyrazole-5-carboxylic acid added portionwise over30 minutes whilst maintaining the reaction temperature below 60° C. Theresulting solution was heated for 18 hours at 60° C., allowed to cool,then poured onto ice. The title compound was obtained as a brown solid(64%). δ (DMSO_(d6)): 1.18 (3H,t), 2.84 (2H,m), 13.72 (1H,s).

[0083] (4d) 3-Ethyl-4-nitro-1H-pyrazole-5-carboxamide

[0084] A solution of the title compound of example (4c) (15.4 g, 0.077mol) in thionylchloride (75 ml) was heated under reflux for 3 hours andthen the cool reaction mixture evaporated under reduced pressure. Theresidue was azeotroped with tetrahydrofuran (2×50 ml) and subsequentlysuspended in tetrahydrofuran (50 ml), then the stirred suspensionice-cooled and treated with gaseous ammonia for 1 hour. Water (50 ml)was added and the resulting mixture evaporated under reduced pressure togive a solid which, after trituration with water and drying by suction,furnished the title compound as a white solid (90%). δ (DMSO_(d6)): 1.17(3H,t), 2.87 (2H,m), 7.40 (1H,s), 7.60 (1H,s), 7.90 (1H,s). LRMS: m/z185 (M+1)⁺.

[0085] (4e)5-Ethyl-4-nitro-1-(2-pyridylmethyl)-1H-pyrazole-3-carboxamide. (CompoundVIIIB)

[0086] Caesium carbonate (1.414 kg, 4.34 mol) was added to a suspensionof the title compound of example (4d) (800 g, 4.34 mol) in acetonitrile(51) and the mixture warmed to 60° C. 2-Chloromethylpyridine (664.7 g,5.23 mol) was added and the reaction heated at 70° C. for 7 hours, thenwater (9.5 l) added and the reaction mixture cooled to 10° C.Granulation of this mixture gave a precipitate which was filtered anddried to afford3-ethyl-4-nitro-1-(pyridin-2-yl)methyl-pyrazole-5-carboxamide (367 g ).Sodium chloride (1.58 kg) was added to the filtrate and the solutionextracted with ethyl acetate (4×1.75 l). The combined organic extractswere distilled to remove approximately 10 l of solvent, toluene (5.6 l )added over 35 minutes to the hot (69-76° C.) solution and the mixtureallowed to cool. The resulting suspension was granulated at <10° C. for30 minutes, filtered, the solid washed with ethyl acetate:toluene(50:50) 600 ml) and dried (60° C.) to afford the title compound (624 g52%) as a light brown solid. δ (DMSO_(d6)): 1.08 (3H,t), 3.02 (2H,q),5.53 (2H,s), 7.34 (2H,m),7.65 (1H,s), 7.82 (1H,m), 7.93 (1H,s), 8.52(1H,d). LRMS: m/z 276 (M+1)⁺.

[0087] (4f)4-Amino-5-ethyl-1-(2-pyridylmethyl)-1H-pyrazole-3-carboxamide. (CompoundIXB)

[0088] A mixture of Lindlar catalyst (2 g ) and the title compound ofexample (4e) (20 g, 72.7 mmol) in ethanol (160 ml) was hydrogenated for48 hours at 345 kPa (50 psi) and 50° C., then cooled and filtered. Thefiltrate was combined with an IMS wash (50 ml) of the filter pad andconcentrated under reduced pressure to a colume of 100 ml. The remainingethanol was removed by distillation, and replaced with ethyl acetateuntil a head temperature of 77° C. had been achieved. The cooled mixturewas granulated at 4° C., filtered and dried to afford the title compound(13.17 g, 73%) as a light brown solid. δ (DMSO_(d6)): 0.90 (3H,t), 2.54(2H,q), 4.48 (2H,s), 5.31 (2H,s), 6.89 (1H,d), 6.95 (1H,s), 7.11 (1H,s),7.28 (1H,m), 7.74 (1H,m), 8.50 (1H,d). LRMS: m/z 246 (M+1)⁺.

[0089] (4g ) 2-Chloro-5-(4-ethyl-1-piperazinylsulphonyl)benzoic acid(Compound VIIB, X=Cl)

[0090] 2-Chloro-5-chlorosulphonylbenzoic acid (51.02 g, 0.2 mol) fromexample (2a) in water was cooled to 5° C. The pH of the reaction wasadjusted to 2.2 using aqueous sodium hydroxide (5M), N-ethylpiperazinewas added and the pH adjustment continued to 5.5. The reaction mixturewas stirred for 12 hours at ambient temperature. The precipitated solidfiltered to afford the title compound. Recrystallisation of the titlecompound from acetone: water affords a solid with m.p. 267-269° C. δ(DMSO): 1.00 (3H, s). 2.50 (2H, m), 2.60 (4H, m), 3.00 (4H, m), 7.75(2H, s), 7.95 (1H, s), m/z (Found: 333 [M+H]⁺, 100% C₁₃H₁₈ClN₂O₄Srequires 333).

[0091] (4h)4-[2-Chloro-5-(4-ethyl-1-piperazinylsulphonyl)benzamido]-5-ethyl-1-(2-pyridylmethyl)-1H-pyrazole-3-carboxamide.(Compound IIB, X=Cl)

[0092] 4-Amino-5-ethyl-1-(2-pyridylmethyl)-1H-pyrazole-3-carboxamide(compound IXB) (4.02 g, 16.4 mmol) was added to a suspension of2-chloro-5-(4-ethyl-1-piperazinylsulphonyl)benzoic acid (5.0 g, 16.4mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride(3.15 g, 16.4 mmol) and 1-hydroxybenzotriazole (2.22 g, 16.4 mmol) indichloromethane (50 ml). The reaction was stirred for 48 hours atambient temperature. The reaction mixture was filtered and the soliddried to afford the title compound (2.26 g, 24.7%) as a white solid m.p.185° C. Found: C, 53.26; H, 5.38; N,17.13. C₂₅H₃₀ClN₇O₄S requires C,53.61; H, 5.40; N, 17.51. δ (DMSO): 0.90 (3H, t), 1.20 (3H, t), 2.30(2H, q), 2.21 (4H, m), 2.70 (2H, q), 2.95 (4H, m), 5.50 (2H, s), 7.10(1H, d), 7.20 (1H, m), 7.30 (2H, m), 7.85 (3H, m), 7.93 (1H, s), 8.55(1H, d), 9.92 (1H, s). m/z (Found: 560.1835 ([M+H]⁺, 65%). C₂₅H₃₁ClN₇O₄Srequires 560.184677).

[0093] (4i)1-Ethyl-4-{3-[3-ethyl-6,7-dihydro-7-oxo-2-(2-pyridylmethyl)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-4-propoxyphenylsulphonyl}piperazine.(Compound IB)

[0094] Potassium t-butoxide (0.90 g, 8.02 mmol) was added to asuspension of the title compound of example 4(h) (1.5 g, 2.68 mmol) inpropan-1-ol (10 ml) and the mixture was heated under reflux for 48hours. The reaction mixture was cooled and the precipitated solid wasfiltered and dried to afford the title compound (1.16 g, 80%).Recrystallisation of the title compound from methyl isobutyl ketoneafforded a solid with m.p. 95° C. δ (CDCl₃): 1.00 (3H, t), 1.12 (3H, t),1.30 (3H, t), 2.02 (2H, m), 2.40 (2H, q), 2.50 (4H, m), 3.10 (6H, m)4.13 (2H, t), 5.70 (2H, s), 7.20 (3H, m), 7.60 (1H, m), 7.80 (1H, m),8.55 (1H,m), m), 8.80 (1H, m), 10.60 (1H, s). m/z (Found: 566.257068([M+H]⁺, 100%). C₂₈H₃₆N₇O₄S. requires 566.257068).

[0095] On sampling the reaction mixture using HPLC, the result suggeststhat the reaction pathway proceeds mainly via intermediate IVB. Theinvention thus provides an excellent process for preparing compounds offormula I which is safe (obviates the need to use carcinogenicalkylating reagents), is economic, utilises readily available startingmaterials, and which combines a novel displacement and ring closurereaction in one reaction vessel.

1) A process for the preparation of a compound of formula (IA) or (IB)below:

comprising reacting a compound of formula (IIa) or (IIb) respectively

 in the presence of ₃₁ OR, wherein R in the case of formation ofcompound (IA) is CH₂CH₃ and R in the case of formation of compound (IB)is CH₂CH₂CH₃, and wherein X is a leaving group: 2) A process as claimedin claim 1 wherein X is selected from the group consisting ofarylsulphonyloxy, C₁-C₄ alkylsulphonyloxy, nitro or halo substitutedbenzenesulphonyloxy, C₁-C₄ perfluoroalkylsulphonyloxy, aroyloxy,substituted aroyloxy, C₁-C₄ perfluoroalkanoyloxy, C₁-C₄ alkanoyloxy,halo; diazonium; C₁-C₄ primary and secondary alkoxy, oxonium,perchloryloxy, quatenaryammonium C₁-C₄ alkylsulphonuloxy,halosulphonyloxy, halonium and diarylsulphonylamino. 3) A process asclaimed in claim 2 wherein X is a halo or methoxy. 4) A process asclaimed in claim 3 wherein X is fluoro, chloro or methoxy. 5) A processas claimed in claim 4 wherein X is fluoro or chloro. 6) A process asclaimed in claim 1 wherein ⁻OR is present with an auxiliary base. 7) Aprocess as claimed in claim 6 wherein the auxiliary base is selectedfrom the group consisting of sterically hindered base, a metal salt of1-methyl piperazine, 1-ethylpiperazine, morpholine, a metal hydride,metal oxide, metal carbonate and metal bicarbonate. 8) A process asclaimed in claim 7 wherein the sterically hindered base is a metal saltof a sterically hindered alcohol or amine. 9) A process as claimed inclaim 8 wherein the metal salt of a sterically hindered alcohol or amineis selected from the group consisting of a secondary or tertiary C₄-C₁₂alkanol, a C₃-C₁₂ cycloalkanol and a secondary or tertiary (C₃-C₈cycloalkyl)C₁-C₆ alkanol, a N-(secondary or tertiary C₃-C₆alkyl)-N-(primary, secondary or tertiary C₃-C₆ alkyl)amine, a N-(C₃-C₈cycloalkyl)-N-(primary, secondary or tertiary C₃-C₆ alkyl)amine, adi(C₃-C₈ cycloalkyl)amine or hexamethyldisilazane1,5-diazabicyclo[4,3,0]non-5-ene 1,8-diazabicyclo[5,4,0]undec-7-ene anda tertiary amine. 10) A process as claimed in claim 9 wherein theauxiliary base is a metal salt of a tertiary alkanol. 11) A process asclaimed in claim 1 wherein the reaction is carried out in an inertsolvent or ROH or a mixture of an inert solvent and ROH. 12) A processas claimed in claim 11 wherein the solvent is selected from the groupconsisting of ethanol, n-propanol, a secondary or tertiary C₄-C₁₂alkanol, a C₃-C₁₂ cycloalkanol, a tertiary C₄-C₁₂ cycloalkanol, asecondary or tertiary (C₃-C₇ cycloalkyl)C₂-C₆ alkanol, a C₃-C₉ alkanone,1,2-dimethoxyethane, 1,2-diethoxyethane, diglyme, tetrahydrofuran,1,4-dioxan, toluene, xylene, chlorobenzene, 1,2-dichlorobenzene,acetonitrile, dimethyl sulphoxide, sulpholane, dimethylformamide,N-methylpyrrolidin-2-one, pyridine, and mixtures thereof. 13) A processas claimed in claim 12 wherein the solvent is selected from the groupconsisting of ethanol, n-propanol, a tertiary C₄-C₁₂ alkanol, a tertiaryC₄-C₁₂ cycloalkanol, a tertiary (C₃-C₇ cycloalkyl)C₂-C₆ alkanol, a C₃-C₉alkanone, 1,2-dimethoxyethane, 1,2-diethoxyethane, diglyme,tetrahydrofuran, 1,4-dioxan, toluene, xylene, chlorobenzene,1,2-dichlorobenzene, acetonitrile, sulpholane, dimethylformamide,N-methylpyrrolidin-2-one, pyridine, and mixtures thereof. 14) A processas claimed in claim 13 wherein the solvent is ethanol or propanol. 15) Aprocess for the preparation of a compound of formula (IA) or (IB) below:

comprising reacting a compound of formula (IIA) or (IIB) respectively

 in the presence of ⁻OR, wherein R in the case of formation of compound(IA) is CH₂CH₃ and R in the case of formation of compound (IB) isCH₂CH₂CH₃, or ⁻OR together with an auxiliary base or ZOR together withan auxiliary base wherein ZOR is a salt of ⁻OR and Z is a cation. 16) Aprocess as claimed in claim 15 for the production of compound (IA)

comprising reacting compound (IIA):

a) with ethanol and auxiliary base, optionally in an inert solvent; orb) with ZOEt and an auxiliary base in ethanol or an inert solvent or amixture thereof; or c) with ZOEt and ethanol or an inert solvent or amixture thereof wherein Z is a cation. 17) A process as claimed in claim15 for the production of compound (IB)

comprising reacting compound (IIB):

a) with propanol and an auxiliary base, optionally in an inert solvent;or b) with ZOPr and an auxiliary base, in propanol or an inert solventor a mixture of both; or c) with ZOPr, and propanol or an inert solventor a mixture of both wherein Z is a cation. 18) A process as claimed inclaim 16 wherein the compound of formula (IIA) is prepared by coupling acompound of formula (VIIA)

with a compound of formula (IXA)

19) A process as claimed in claim 17 wherein a compound of formula (IIB)is prepared by coupling a compound of formula (VIIB)

with a compound of formula (IXB)

20) A process as claimed in claim 18 wherein a compound of the formula(VIIA) is formed by coupling a compound of formula (VIA) withN-methylpiperazine

21) A process as claimed in claim 19 wherein a compound of formula(VIIB) is formed by coupling a compound of formula (VIA) withN-ethylpiperazine.

22) A compound of formula (IIA) or (IIB):

wherein X is a leaving group. 23) A compound of formula (IIIA) or(IIIB):

wherein X is a leaving group. 24) A compound of formula (VIIA) or (VIIB)

wherein X is a leaving group. 25) A compound according to claim 22wherein X is selected from the group consisting of fluoro, chloro andmethoxy. 26) A compound according to claim 23 wherein X is selected fromthe group consisting of fluoro, chloro and methoxy. 27) A compoundaccording to claim 24 wherein X is selected from the group consisting offluoro, chloro and methoxy.